Effectiveness of second line hypoglycemic medications among veterans Guidelines recommend metformin as the initial treatment for diabetes mellitus (DM) unless contraindicated, and also recommend a treatment target glycosylated hemoglobin (HbA1c) of <7%. Many patients require a second agent to reach these goals; however, little guidance is given for the selection of a second agent. Clinical judgement must be utilized and HbA1c goals of less than 7% may not be appropriate for some patients, particularly elderly patients and those with cardiovascular disease (CVD). While randomized trials often generate efficacy data, some trials do not include long-term outcomes; have a narrow spectrum of patients and may not compare relevant exposures to each other. Observational studies can help fill knowledge gaps and include diverse populations. This proposal will focus on real world decisions faced by clinicians and patients. We propose to answer key questions. Among patients using a single agent for the care of their diabetes and whose HbA1C is above goal on metformin monotherapy: What is the impact of insulin initiation compared to initiation of a second oral antidiabetic drug (OAD) on glycemic control, cardiovascular and renal outcomes? Among the subgroup of patients with pre-existing heart disease, what is the impact of no intensification versus intensification with any agent on the risk for cardiovascular and renal outcomes? This project will utilize national VHA data (Corporate Data Warehouse- Vital Signs File; pharmacy, SAS Medical datasets, VIReC Medicare data and VHA Vital status files) and National Death Index data to construct a national cohort of veterans with DM initially treated with metformin for a new diagnosis of DM (inception cohort). The proposed study follows this inception cohort to determine the patterns of drug use at the time they fail first line therapy (HbA1c >7.0% while on metformin). Given that metformin is recommended as first line therapy among many patients, we will study the addition of drugs to metformin to determine which regimen is most beneficial to risk intermediate outcomes such as HbA1C and long term outcomes such as CVD and renal outcomes. Persons included are aged >18 years, utilize the VA healthcare system between 10/30/2000 to 09/30/2010. The following exposures will be examined: 0= no DM drug, 1= metformin only, 2= metformin + insulin, 3= metformin + sulfonylurea 4= metformin+ pioglitazone 5=metformin+ rosiglitazone and 6= none of the above. Aim 1 will examine patient characteristics at the time of therapy initiation. Examined attributes will include administrative covariates plus those collected through chart review (Frailty index, diet, exercise, metformin adherence, and patient/provider information about treatment choice, and co-morbidities). We will use this information to help construct cohorts with similar covariates. Additionally, sensitivity analyses will quantify the size of a confounder that would explain our study findings. Aim 2 will examine glycemic effects of the second agent: the proportion who reach HbA1c of <7% and mean difference in HbA1c at 1 year as well as durability of glycemic control among those who have a second agent added and adverse effects including serious hypoglycemia. Aim 3 will examine the time to clinical outcomes including CVD (AMI, Stroke), chronic kidney disease (CKD) and all cause and cardiovascular mortality. We will use the marginal structural Cox proportional hazards models (MSM) using stabilized Inverse probability treatment weights (IPTW). The IPTW will be modeled using multinomial logistic regression incorporating fixed (baseline) and time-dependent exposures and covariates. The final stabilized weights used in the proposed MSMs will be calculated as the product of the treatment and censoring weights given each patient's static and time varying covariates over the previous time-points. Sensitivity analysis will be conducted to determine the effect of unmeasured confounders on risk of the outcome. The research team is poised to conduct a rigorous study on the safety and clinical effectiveness of second line therapies for DM.